Opposing Roles for Microglia in the Young and Aged Neurogenic Niche

小胶质细胞在年轻和老年神经源性生态位中的相反作用

• 批准号: 10207796
• 负责人: Erzsebet Kokovay
• 金额: $ 33.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207796
• 关键词: 3-Dimensional; Ablation; Adult; Age; Aging; Apoptotic; Architecture; Astrocytes; Blood Vessels; Brain; Brain Injuries; Cell Count; Cell Lineage; Cell Maintenance; Cell Separation; Cell Survival; Cells; Conditioned Culture Media; Data; Endothelium; Flow Cytometry; Functional disorder; Goals; Home; Homeostasis; Image Analysis; Immune; Impairment; In Vitro; Inflammation; Inflammatory; Infusion procedures; Interleukin-1 beta; Interleukin-6; Intervention; Knowledge; Learning; Life; Maintenance; Measures; Memory; Microglia; Molecular; Morphology; Mus; Neuronal Differentiation; Neurons; Oligodendroglia; Phagocytosis; Pharmacology; Phenotype; Play; Positioning Attribute; Property; Publishing; Recovery; Rest; Role; Signal Transduction; Source; Supporting Cell; Surface; TNF gene; Testing; Therapeutic; Tissues; Transgenic Organisms; Ventricular; age related; aged; aging brain; brain cell; brain repair; cell type; cytokine; density; in vivo; inflammatory marker; lateral ventricle; motor deficit; nerve stem cell; neuroblast; neurogenesis; neuroregulation; novel; olfactory bulb; relating to nervous system; stem; stem cell biology; stem cell function; stem cell niche; stem cell proliferation; stem cells; subventricular zone

Project Summary Neural stem cell/progenitors cells give rise to mature neurons, astrocytes and oligodendrocytes throughout life. However, neurogenesis rapidly declines during aging and the mechanism for age-dependent neural stem cell dysfunction is not clear. The ventricular-subventricular zone (V- SVZ), lining the lateral ventricle, is home to the largest pool of neural stem cells in the murine brain. We have found that microglia, the innate immune cells of the brain, are prominently positioned throughout the young and aged V-SVZ niche. During aging, microglia undergo a morphological and phenotypical shift from a resting state to a pro-inflammatory state. Preliminary data suggest that secreted molecules from young microglia support proliferation and neuronal differentiation in vitro. In contrast, microglia isolated from aged mice appear to lose this influence on proliferation in vitro. Together, these data suggest microglia play a critical age- dependent role in regulating neurogenesis. Although microglia are known to be important in phagocytosis of neuroblasts, their influence on type B neural stem cells, type C transit amplifying cells and niche cytoarchitecture is essentially unknown. Using 3-dimensional image analysis of niche cytoarchitecture and flow activated cell sorting (FACS), we will test the hypothesis that microglia have opposing roles in the young and aged neurogenic niche. In aim 1, we will pharmacologically and genetically deplete microglia from the young neurogenic niche and interrogate the impact on neurogenesis, Type B, C and neuroblast cell survival as well as number, proliferation and position near the vascular compartment. In aim 2, we will use heterochronic infusion of secreted molecules from young and aged microglia to directly test if these molecules have opposing roles in neurogenesis. In aim 3, we will test if mitigating the inflammatory phenotype of aged microglia restores neural stem/progenitor cell function. We will also explore novel molecular candidates for microglia derived secreted molecules that support or hinder neurogenesis. Understanding how the microglia activation state regulates neurogenesis will have far-reaching consequences. It is widely accepted that V-SVZ neural stem cells and their progeny contribute to brain repair. Thus, understanding how microglia contribute to neurogenesis during tissue homeostasis and aging will not only further our basic understanding of neurogenesis but will help in the eventual goal of using neural stem/progenitor cells in brain therapeutics.

项目总结